The blood-brain barrier (BBB) is a unique feature of the central nervous system (CNS) which isolates the brain from the systemic blood circulation. To maintain the homeostasis of the CNS, the BBB prevents access to the brain of many substances circulating in the blood.
The BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages, and a basal lamina. Compared to other tissues, brain endothelia have the most intimate cell-to-cell connections: endothelial cells adhere strongly to each other, forming structures specific to the CNS called “tight junctions” or zonula occludens. They involve two opposing plasma membranes which form a membrane fusion with cytoplasmic densities on either side. These tight junctions prevent cell migration or cell movement between endothelial cells. A continuous uniform basement membrane surrounds the brain capillaries. This basal lamina encloses contractile cells called pericytes, which form an intermittent layer and probably play some role in phagocytosis activity and defense if the BBB is breached. Astrocytic end feet, which cover the brain capillaries, build a continuous sleeve and maintain the integrity of the EBB by the synthesis and secretion of soluble growth factors (e.g., gamma-glutamyl transpeptidase) essential for the endothelial cells to develop their BBB characteristics.
PCT Patent Publication WO 01/85094 to Shalev and Gross, which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for modifying a property of a brain of a patient, including electrodes applied to a sphenopalatine ganglion (SPG) or a neural tract originating in or leading to the SPG. A control unit drives the electrodes to apply a current capable of inducing (a) an increase in permeability of a blood-brain barrier (BBB) of the patient, (b) a change in cerebral blood flow of the patient, and/or (c) an inhibition of parasympathetic activity of the SPG.
U.S. Pat. No. 5,756,071 to Mattern et al., which is incorporated herein by reference, describes a method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier. The patent describes a metering spray designed for pernasal application, the spray containing at least one sex hormone or at least one metabolic precursor of a sex hormone or at least one derivative of a sex hormone or combinations of these, excepting the precursors of testosterone, or at least one biogenic amine, with the exception of catecholamines.
U.S. Pat. No. 5,752,515 to Jolesz et al., which is incorporated herein by reference, describes apparatus for image-guided ultrasound delivery of compounds through the blood-brain barrier. Ultrasound is applied to a site in the brain to effect in the tissues and/or fluids at that location a change detectable by imaging. At least a portion of the brain in the vicinity of the selected location is imaged, e.g., via magnetic resonance imaging, to confirm the location of that change. A compound, e.g., a neuropharmaceutical, in the patient's bloodstream is delivered to the confirmed location by applying ultrasound to effect opening of the blood-brain barrier at that location and, thereby, to induce uptake of the compound there.
PCT Publication WO 01/97905 to Ansarinia, which is incorporated herein by reference, describes a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode on or proximate to at least one of the patient's SPG, sphenopalatine nerves, or vidian nerves, and activating the electrode to apply an electrical signal to such nerve. In a further embodiment for treating the same conditions, the electrode used is activated to dispense a medication solution or analgesic to such nerve. The '905 publication also describes surgical techniques for implanting the electrode.
U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein by reference, describes a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode adjacent to or around a sinus, the dura adjacent a sinus, or falx cerebri, and activating the electrode to apply an electrical signal to the site. In a further embodiment for treating the same conditions, the electrode dispenses a medication solution or analgesic to the site. The '079 patent also describes surgical techniques for implanting the electrode.
U.S. Pat. No. 6,294,544 to Araie et al., which is incorporated herein by reference, describes a peripheral ocular circulation ameliorant which contains dihydropyridines, for treating visual field defects associated with normal intraocular pressure glaucoma as well as for optic neuropathy, retinopathy, and retinal-degeneration diseases.
U.S. Pat. No. 5,431,907 to Abelson et al., which is incorporated herein by reference, describes the administration of calcium channel blocking agents to the eye to treat ischemic disorders of the retina and associated tissues of the posterior segment of the eye, by increasing blood flow to these tissues.
U.S. Pat. No. 6,451,799 to Ogawa et al., which is incorporated herein by reference, describes an ocular circulation ameliorant which contains a 1,4-dihydropyridine derivative, for treating glaucoma, particularly normal tension glaucoma caused by ocular circulation disorder and retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, retinal vein occlusion, diabetic retinopathy, ischemic optic neuropathy, retinochoroidal disease following choroidal lesion, and retinochoroidal disease associated with systemic disease.
The following references, which are incorporated herein by reference, may be useful:    Delepine L, Aubineau P, “Plasma protein extravasation induced in the rat dura mater by stimulation of the parasympathetic sphenopalatine ganglion,” Experimental Neurology, 147, 389–400 (1997)    Hara H, Zhang Q J, Kuroyanagi T, Kobayashi S, “Parasympathetic cerebrovascular innervation: An anterograde tracing from the sphenopalatine ganglion in the rat,” Neurosurgery, 32, 822–827 (1993)    Jolliet-Riant P, Tillement J P, “Drug transfer across the blood-brain barrier and improvement of brain delivery,” Fundam. Clin. Pharmacol., 13, 16–25 (1999)    Kroll R A, Neuwelt E A, “Outwitting the blood brain barrier for therapeutic purposes: Osmotic opening and other means,” Neurosurgery, 42, 1083–1100 (1998)    Sanders M, Zuurmond W W, “Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: A 12–70 month follow-up evaluation,” Journal of Neurosurgery, 87, 876–880 (1997)    Syelaz J, Hara H, Pinard E, Mraovitch S, MacKenzie E T, Edvinsson L, “Effects of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat,” Journal of Cerebral Blood Flow and Metabolism,” 8, 875–878 (1988)    Van de Waterbeemd H, Camenisch G, Folkers G, Chretien J R, Raevsky O A, “Estimation of blood brain barrier crossing of drugs using molecular size and shape and h bonding descriptors,” Journal of Drug Targeting,” 6, 151–165, (1998)    Suzuki N, Hardebo J E, Kahrstrom J, Owman C, “Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat,” Journal of Cerebral Blood Flow and Metabolism, 10, 383–391 (1990)    Suzuki N, Hardebo J E, Kahrstrom J, Owman C H, “Effect on cortical blood flow of electrical stimulation of trigeminal cerebrovascular nerve fibres in the rat,” Acta Physiol. Scand., 138, 307–315 (1990)    Major A, Silver W, “Odorants presented to the rat nasal cavity increase cortical blood flow,” Chem. Senses, 24, 665–669 (1999)    Fusco B M, Fiore G, Gallo F, Martelletti P, Giacovazzo M, “‘Capsaicin-sensitive’ sensory neurons in cluster headache: pathophysiological aspects and therapeutic indications,” Headache, 34, 132–137 (1994)    Lambert G A, Bogduk N, Goadsby P J, Duckworth J W, Lance J W, “Decreased carotid arterial resistance in cats in response to trigeminal stimulation,” Journal of Neurosurgery, 61, 307–315 (1984)    Silver W L, “Neural and pharmacological basis for nasal irritation,” in Tucker W G, Leaderer B P, Mølhave L, Cain W S (eds), Sources of Indoor Air Contaminants, Ann. NY Acad. Sci., 641, 152–163 (1992)    Silver W, “Chemesthesis: the burning questions,” ChemoSense, Vol. 2, 1–2 (1999)    Devoghel J C, “Cluster headache and sphenopalatine block,” Acta Anaesthesiol Belg., 32 (1):101–7 (1981)